Former smokers remain at risk for lung cancer after smoking cessation, and make up 50% of new lung cancer diagnoses. Tobacco exposure leads to development of preneoplastic lesions in the airways, which progress through several stages of histologic severity, and which can persist after smoking cessation. Progress in lung cancer prevention was achieved with iloprost, a prostacyclin analog that works mainly through activation of the peroxisomal proliferator-activated receptor ? (PPAR?) pathway. In a randomized placebo-controlled trial, oral iloprost treatment in high-risk former smokers improved both airway histology scores and the dysplasia index compared to placebo. This finding shows that reduction in the burden of airway premalignancy is feasible with PPAR? agonists such as iloprost. Biomarkers that predict potential for persistence of preneoplasias and/or resistance to iloprost would be useful in suggesting agents that might be combined with iloprost to improve efficacy. In this R21 application, we will examine expression of proteins in the estrogen receptor (ER) pathway for association with severity or persistence of dysplasia found in high-risk smokers (Aim 1). The estrogen receptor (ER) pathway has been strongly implicated in lung cancer and is a candidate pathway for identification of aggressive preneoplastic lesions in the airway, based on our preliminary data. We will also determine the efficacy of an anti-estrogen alone and in combination with PPAR? activation in chemoprevention studies in animals, to obtain preclinical data in support of testing this combination in human trials (Aim 2). Finally, we will determine if ER pathway proteins are associated with resistance to the PPAR? agonist pioglitazone in biospecimens collected from an on-going chemoprevention clinical trial, to test the predictive value of ER pathway proteins as biomarkers of dysplasia persistence and/or response to a PPAR? agonist (Aim 3).